1. Field of the Invention
The present invention relates to methods and compositions for preventing thrombosis in or caused by the use of liquid delivery systems, e.g., catheter and port systems.
2. Description of the Background Art
Delivery systems are widely used in medicine for introducing liquid material which might include medicaments, nutrition, or other active agents to a patient. Such systems frequently involve the use of catheters which, for many applications, are surgically or intravenously located and stitched into place for long-term administration of the desired material. Typical systems include central catheters such as may be used for total parenteral nutrition (TPN), e.g. when treating short bowel syndrome (for the duration of a patient's life), catheters and drains in hemodialysis and peritoneal dialysis for those with terminal kidney failure, and subcutaneously implanted port systems such as may be used in the treatment of malignant conditions.
One problem associated with the use of liquid delivery systems, e.g., port or catheter-based systems, is that these can give rise to infections which in turn may lead to infected intra-atrial thrombus, embolism, phlebitis, sepsis, endocarditis of the mitral valve, ostium infection, septic lung abscesses, and/or purulent septic pulmonary infarction. One solution to this problem is the use of solutions containing the antibacterial agents taurolidine and/or taurultam. For example, long term continuous infusion of taurolin solutions to prevent septic complications in patients receiving parenteral nutrition has been proposed (see Blenkharn, Clinical Nutrition 6(1):35–38, 1987 and Johnston et al., Clinical Nutrition 12(6): 365–358, 1993). More recently in WO98/28027, taurolin solutions have been suggested for use as a temporary seal or flush to prevent or reduce sepsis in port systems or catheters.
Taurolidine and/or taurultam are particularly effective in combating not only infecting bacteria but also in preventing the release of bacterial toxins as well as inactivating any that may be present. These compounds are methylol transfer agents and exert their antibacterial activity by reacting with the bacterial cell wall components and forming covalent bonds. Despite, therefore, the possibility of quite lengthy residence time in the delivery system, they have been found not to cause any build-up of resistance.
Another problem associated with the use of liquid delivery systems is the potential for blockage of the delivery tubes due to the formation of a coating of fibrin sheath deposits, especially during periods of long term use. The coating starts around a catheter with a thrombus containing fibrin, and progresses into vascularized, fibrous connective tissue. This sheath contains fibroblasts and collagen. Fibrinolytic agents cannot dissolve connective tissue.
Fibrin and/or collagen deposits can result in a significant narrowing of the delivery tubes and, in severe cases, total occlusion. The consequences of the formation of fibrin and/or collagen deposits in liquid delivery systems are therefore clearly dangerous. Moreover, removal or replacement of the delivery system may well have to be carried out operatively, necessitating a further stay in hospital for the patient and further expense.
Removal of a thrombus, especially when located at catheter closures, is difficult and cannot be resolved by fibrinolytic agents such as urokinase, streptokinase, etc., and the following complications are likely to occur. In cavacatheters complications may include thrombosis, embolism, phlebitis and sepsis. In femoral catheters complications may include thrombosis, lethal cases of pulmonary embolism and sepsis. In subclavial-catheters complications may include puncture-proof blockage, thrombosis due to false catheter position, septic complications, total blockage of the vena subclava, and thrombotic changes caused by intima-damage (parietal thromboses between catheter- and vascular wall).
There remains a need in the art for methods and compositions for preventing thrombosis in liquid delivery systems.